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Traumatic-noise-induced hair cell death and hearing loss is mediated by activation of CaMKKβ

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Abstract

Background

The Ca2+/calmodulin-dependent protein kinase kinases (CaMKKs) are serine/threonine-directed protein kinases that are activated following increases in intracellular calcium, playing a critical role in neuronal signaling. Inner-ear-trauma-induced calcium overload in sensory hair cells has been well documented in the pathogenesis of traumatic noise-induced hair cell death and hearing loss, but there are no established pharmaceutical therapies available due to a lack of specific therapeutic targets. In this study, we investigated the activation of CaMKKβ in the inner ear after traumatic noise exposure and assessed the prevention of noise-induced hearing loss (NIHL) with RNA silencing.

Results

Treatment with short hairpin RNA of CaMKKβ (shCaMKKβ) via adeno-associated virus transduction significantly knocked down CaMKKβ expression in the inner ear. Knockdown of CaMKKβ significantly attenuated noise-induced hair cell loss and hearing loss (NIHL). Additionally, pretreatment with naked CaMKKβ small interfering RNA (siCaMKKβ) attenuated noise-induced losses of inner hair cell synapses and OHCs and NIHL. Furthermore, traumatic noise exposure activates CaMKKβ in OHCs as demonstrated by immunolabeling for p-CaMKI. CaMKKβ mRNA assessed by fluorescence in-situ hybridization and immunolabeling for CaMKKβ in OHCs also increased after the exposure. Finally, pretreatment with siCaMKKβ diminished noise-induced activation of AMPKα in OHCs.

Conclusions

These findings demonstrate that traumatic-noise-induced OHC loss and hearing loss occur primarily via activation of CaMKKβ. Targeting CaMKKβ is a key strategy for prevention of noise-induced hearing loss. Furthermore, our data suggest that noise-induced activation of AMPKα in OHCs occurs via the CaMKKβ pathway.

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Fig. 1
Fig. 2
Fig. 3

taken from the apical, middle, basal, and hook turns of whole mount surface preparations immunolabeled with myosin VIIa and then stained with DAB to illustrate OHCs and IHCs. OHC 1, 2, 3, and IHC indicate three rows of outer hair cells and one row of inner hair cells. Counts of OHC loss are shown in Fig. 4A. These images are representative of six mice for each group. Scale bar = 10 µm

Fig. 4

taken from the lower basal cochlear turn. Scale bar = 20 µm. C Noise-induced auditory threshold shifts are significantly reduced in AAV-shCaMKKβ mice compared to AAV-shCtrl mice calculated as baseline ABR thresholds subtracted from thresholds measured 14 d after noise exposure for each individual mouse. Data are presented as individual mice ± SD. D Noise-diminished DPOAE amplitudes are significantly reversed by shCaMKKβ application measured 14 d after noise exposure. Data are presented as means ± SD. The detailed statistical values are listed in Table S2; *indicates the p value of the comparison between shCtrl + noise exposure vs shCaMKKβ + noise exposure, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001

Fig. 5

taken from the basal turn at 4 mm from the apex and are representative of 5–7 mice for each group. Scale bar = 10 µm. F Counts of OHC loss along the entire length of the cochlear duct show that pretreatment with siCaMKKβ significantly reduced noise-induced OHC loss. Data are presented as means + SD. Detailed statistical values are listed in Table S4. The number of animals in each group is indicated in the labels, *indicates the p value for the comparison between siCtrl + PTSN vs siCaMKKβ + PTSN. *p < 0.05, **p < 0.01, ***p < 0.001

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Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Abbreviations

AAV:

Adeno-associated virus

ABR:

Auditory brainstem response

AMPKα:

AMP-dependent protein kinase α subunit

CaMKKβ:

Ca2+/calmodulin-dependent protein kinase kinase-β

DPOAE:

Distortion product otoacoustic emissions

eGFP:

Enhanced green fluorescent protein

FISH:

Fluorescent in-situ hybridization

HCs:

Hair cells

IHCs:

Inner hair cells

IP:

Intraperitoneal injection

KO:

Knockout mice

LKB1:

Liver kinase B1

MET:

Mechanoelectrical transducer channels

NIHL:

Noise-induced hearing loss

OHCs:

Outer hair cells

PBS:

Phosphate-buffered saline

PBS-T:

PBS with 0.1% Tween 20

PTS:

Permanent threshold shift

PTSN:

PTS-noise

ROS:

Reactive oxygen species

RWM:

Round window membrane

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

SPL:

Sound pressure level

siRNA:

Small interfering RNA silencing

shRNA:

Short hairpin RNA silencing

siControl:

Scrambled siRNA

TTS:

Temporary threshold shift

TDT:

Tucker Davis Technology

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Acknowledgements

We thank Dr. Jochen Schacht for his valuable comments on the manuscript. We also thank Dr. Yuan Shao in the MUSC Biorepository & Tissue Analysis Shared Resource for technical assistance with in-situ hybridization RNAscope and Andra Talaska for proofreading of the manuscript.

Funding

The research project described was supported by grant R01 DC009222 from the National Institute on Deafness and Other Communication Disorders, National Institutes of Health. All experiments described in this manuscript were conducted in the WR Building at Medical University of South Carolina in renovated space supported by grant C06 RR014516. Animals were housed in MUSC CRI animal facilities supported by grant C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resources.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, The Medical University of South Carolina, Walton Research Building, Room 403-E, 39 Sabin Street, Charleston, SC, 29425, USA

    Fan Wu, Kayla Hill, Qiaojun Fang, Zuhong He, Hongwei Zheng, Xianren Wang, Hao Xiong & Su-Hua Sha

  2. Department of Otolaryngology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

    Fan Wu

  3. School of Life Sciences and Technology, Southeast University, Nanjing, 210096, China

    Qiaojun Fang

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  1. Fan Wu
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Contributions

FW, KH, QF authors have contributed equally to this work. SS designed research; FW, KH, QF, ZH, HZ, XW, and HX performed research; FW, KH, QF, and SS analyzed data; FW, KH, and SS wrote the paper. All authors have reviewed the contents of the manuscript, approve of its contents, and validate the accuracy of the data.

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Correspondence to Su-Hua Sha.

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Wu, F., Hill, K., Fang, Q. et al. Traumatic-noise-induced hair cell death and hearing loss is mediated by activation of CaMKKβ. Cell. Mol. Life Sci. 79, 249 (2022). https://doi.org/10.1007/s00018-022-04268-4

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